This is an application for a 5 year NIGMS Mentored Clinical Scientist Development Award to study the molecular and cellular response to pulmonary contusion. The proposed research complements the Pi's clinical expertise in the area of trauma surgery and human pulmonary contusion. The application incorporates a formal education plan to complete a PhD in Molecular Medicine and development of a research project utilizing a mouse model of blunt chest trauma and pulmonary contusion. Primary mentorship will be provided by Dr. Charles E. McCall, an established investigator, in conjunction with other members of the Pi's PhD candidate advisory committee. Training and career development activities with extramural mentors is also proposed. PROJECT SUMMARY: Blunt chest trauma and associated pulmonary contusion is a common injury, affecting 10-17% of all trauma admissions and estimates of mortality are 10-25%. The mechanisms responsible for pathology associated with pulmonary contusion are poorly understood but are known to cause wide ranging clinical dysfunction from mild dyspnea to prolonged mechanical ventilation, infection (pneumonia), local organ failure (Acute Respiratory Distress Syndrome, ARDS), and remote organ failure (Multiple Organ Dysfunction/Failure, MODS/MOF). Some dysfunction is a direct result of pulmonary damage; however, there is strong evidence that lung injury induces inflammatory mediators and activates immune cells, that can be correlated with the severity of the clinical pathology and lung dysfunction. We hypothesize that toll like receptors mediate a response to pulmonary contusion by activating immune cells and inducing inflammatory mediators. The objectives of this research plan are to identify the mechanisms responsible for (1) TLR dependent activation of inflammatory responses following blunt chest trauma and (2) neutrophil recruitment to the injured lung after pulmonary contusion. PROJECT RELEVANCE: This study will provide insight into the molecular and cellular response to pulmonary contusion. These results may expand our understanding of the pathogenesis of pulmonary contusion, a common and potentially lethal injury associated with blunt chest trauma. This increased understanding may help to develop new therapy paradigms to treat patients with pulmonary contusions. [unreadable] [unreadable] [unreadable]